U.S. patent application number 11/558782 was filed with the patent office on 2008-06-05 for synergistic combinations of norketamine and opioid analgesics.
This patent application is currently assigned to Yaupon Therapeutics, Inc.. Invention is credited to Peter A. Crooks, Joseph R. Holtman.
Application Number | 20080132531 11/558782 |
Document ID | / |
Family ID | 35516773 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080132531 |
Kind Code |
A1 |
Holtman; Joseph R. ; et
al. |
June 5, 2008 |
SYNERGISTIC COMBINATIONS OF NORKETAMINE AND OPIOID ANALGESICS
Abstract
The present invention relates to methods of alleviating pain
with the administration of norketamine with a narcotic. More
particularly, the invention provides a method of alleviating pain
through the administration of a dose of norketamine, which, if
administered alone would provide sub-optimal analgesic relief, yet
provides analgesic relief when combined with a narcotic. In some
embodiments, the combination of norketamine with a narcotic,
further allows for the administration of a dose narcotic, which
would be sub-optimal if used alone, but provides adequate pain
relief in combination with norketamine. The invention relates to
self-management of pain on an outpatient basis comprising
administering via conventional routes, including transdermal,
nasal, rectal, oral, transmucosal, intravenous, intramuscular, and
other routes, one or more doses of norketamine/opioid compositions
effective to alleviate pain to a subject suffering from pain. Uses
of norketamine/opioid compositions would also apply, to treating
headaches, drug abuse, mood and anxiety disorders, as well as
other, neuropsychiatric disorders, both motoric and cognitive, such
as Alzheimer's disease, Parkinson's syndrome, which are thought to
be caused by neurodegeneration.
Inventors: |
Holtman; Joseph R.;
(Lexington, KY) ; Crooks; Peter A.;
(Nicholasville, KY) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Yaupon Therapeutics, Inc.
|
Family ID: |
35516773 |
Appl. No.: |
11/558782 |
Filed: |
November 10, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60735921 |
Nov 14, 2005 |
|
|
|
Current U.S.
Class: |
514/282 ;
514/183; 514/281; 514/326; 514/329; 514/646 |
Current CPC
Class: |
A61K 31/473 20130101;
A61K 31/473 20130101; A61P 23/00 20180101; A61K 31/485 20130101;
A61P 25/04 20180101; A61P 29/00 20180101; A61K 31/485 20130101;
A61P 25/16 20180101; A61K 45/06 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61P 25/28 20180101; A61P 25/00
20180101 |
Class at
Publication: |
514/282 ;
514/646; 514/329; 514/326; 514/281; 514/183 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61P 29/00 20060101 A61P029/00; A61P 25/00 20060101
A61P025/00; A61K 31/135 20060101 A61K031/135; A61K 31/445 20060101
A61K031/445; A61K 31/4355 20060101 A61K031/4355 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 11, 2005 |
GB |
0523031.3 |
Claims
1. A method of alleviating pain in a subject in need thereof
comprising administering to a subject in need thereof an effective
amount of a first active ingredient and an effective amount of a
second active ingredient, the first active ingredient being
selected from (S)-norketamine, (R)-norketamine, their respective
salts, solvates, or prodrugs, or any combinations thereof, the
second active ingredient being selected from an opioid, provided
that the effective amount of the first active ingredient, if
administered in the absence of the second active ingredient, would
be insufficient to exert an optimal analgesic effect on the
subject.
2. The method of claim 1 in which the effective amount of the
second active ingredient, if administered in the absence of the
first active ingredient, would be insufficient to exert an optimal
analgesic effect on the subject.
3. The method of claim 1 in which the first and second active
ingredients are administered separately.
4. The method of claim 1 in which the first and second active
ingredients are administered together.
5. The method of claim 1 in which the second active ingredient is
selected from fentanyl, sefentanil, alfentanil, morphine,
hydromorphine, oxymorphine, methadone, oxycodone, hydrocodone,
remifentanil, dihydrocodeine, ethylmorphine, nalbuphine,
buprenorphine, dihydromorphine, normorphine, dihydroetorphine,
butorphanol, pentazocine, phenazocine, codeine, meperidine,
propoxyphene, tramadol, levorphanol, L-acetylmethadol,
diacetylmorphine (heroin), etorphine, normethadone, noroxycodone,
and norlevorphanol.
6. The method of claim 1 in which the second active ingredient is
morphine.
7. A method of inhibiting tolerance to a narcotic analgesic in a
subject in need thereof comprising co-administering to a subject in
need thereof (S)-norketamine, (R)-norketamine, their respective
salts, solvates, or prodrugs, or any combinations thereof with a
narcotic analgesic, the narcotic analgesic, if administered in the
absence of the (S)-norketamine, (R)-norketamine, their respective
salts, solvates, or prodrugs, or any combinations thereof, would
induce in the subject a tolerance for the narcotic analgesic.
8. The method of claim 7 in which the narcotic analgesic would
induce in the subject a tolerance for the narcotic analgesic after
about one week of daily administration.
9. The method of claim 7 in which the narcotic analgesic is
selected from fentanyl, sefentanil, alfentanil, morphine,
hydromorphine, oxymorphine, methadone, oxycodone, hydrocodone,
remifentanil, dihydrocodeine, ethylmorphine, nalbuphine,
buprenorphine, dihydromorphine, normorphine, dihydroetorphine,
butorphanol, pentazocine, phenazocine, codeine, meperidine,
propoxyphene, tramadol, levorphanol, L-acetylmethadol,
diacetylmorphine (heroin), etorphine, normethadone, noroxycodone,
and norlevorphanol.
10. The method of claim 1 in which the narcotic analgesic is
morphine.
11. The method of claim 7 in which the effective amount of the
(S)-norketamine, (R)-norketamine, their respective salts, solvates,
or prodrugs, or any combinations thereof would be insufficient to
exert an optimal analgesic effect on the subject.
12. A method of alleviating pain in a subject in need thereof
comprising administering to the subject a therapeutically effective
amount of a first active ingredient and a therapeutically effective
amount of a second active ingredient, the first active ingredient
being selected from (S)-norketamine, (R)-norketamine, their
respective pharmaceutically acceptable salts, solvates, or
prodrugs, or any combinations thereof, the second active ingredient
being selected from an opioid, provided that (A) the
therapeutically effective amount of the first active ingredient, if
administered in the absence of the second active ingredient, would
be insufficient to exert an optimal analgesic effect on the
subject, (B) the therapeutically effective amount of the second
active ingredient, if administered in the absence of the first
active ingredient, would be insufficient to exert an optimal
analgesic effect on the subject, or (C) the therapeutically
effective amounts of both the first active ingredient and the
second active ingredient, if each is administered alone, would be
insufficient to exert an optimal analgesic effect on the
subject.
13. The method of claim 12 in which the therapeutically effective
amount of the second active ingredient, if administered in the
absence of the first active ingredient, would be insufficient to
exert an optimal analgesic effect on the subject.
14. The method of claim 12 in which the first and second active
ingredients are administered separately.
15. The method of claim 12 in which the first and second active
ingredients are administered together.
16. The method of claim 12 in which the second active ingredient is
selected from fentanyl, sefentanil, alfentanil, morphine,
hydromorphine, oxymorphine, methadone, oxycodone, hydrocodone,
remifentanil, dihydrocodeine, ethylmorphine, nalbuphine,
buprenorphine, dihydromorphine, normorphine, dihydroetorphine,
butorphanol, pentazocine, phenazocine, codeine, meperidine,
propoxyphene, tramadol, levorphanol, L-acetylmethadol,
diacetylmorphine (heroin), etorphine, normethadone, noroxycodone,
and norlevorphanol.
17. The method of claim 12 in which the second active ingredient is
morphine or oxycodone.
18. A method of treating a neurodegenerative or neuropsychiatric
disorder in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of a first active
ingredient and a therapeutically effective amount of a second
active ingredient, the first active ingredient being selected from
(S)-norketamine, (R)-norketamine, their respective pharmaceutically
acceptable salts, solvates, or prodrugs, or any combinations
thereof, the second active ingredient being selected from an
opioid, provided that (A) the therapeutically effective amount of
the first active ingredient, if administered in the absence of the
second active ingredient, would be insufficient to exert an optimal
analgesic effect on the subject, (B) the therapeutically effective
amount of the second active ingredient, if administered in the
absence of the first active ingredient, would be insufficient to
exert an optimal analgesic effect on the subject, or (C) the
therapeutically effective amounts of both the first active
ingredient and the second active ingredient, if each is
administered alone, would be insufficient to exert an optimal
analgesic effect on the subject.
19. The method of claim 18 in which the disorder is Alzheimer's
disease, Parkinson's syndrome or neurodegeneration.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application claims priority from United Kingdom
Application 0523031.3, filed Nov. 11, 2005 and U.S. Provisional
Application 60/735,921, filed Nov. 14, 2005, both of which are
incorporated by reference herein in their entireties.
TECHNICAL FIELD
[0002] The present invention generally relates to analgesic drugs
and methods of use their use. More particularly, the invention
relates to pharmaceuticals comprising a combination of norketamine
and a narcotic and methods of their use for the management of
chronic pain.
BACKGROUND
[0003] Norketamine (2-(2-chlorophenyl)-2-amino-cyclohexanone) is
one of the principal metabolic products of ketamine
(2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone), which is a
general anesthetic used by anesthesiologists, veterinarians, and
researchers. Current pharmaceutical compositions of ketamine are
racemic mixtures of S- and R-ketamine, though S-ketamine has been
found recently to be twice as potent as R-ketamine and to allow
faster recovery with fewer negative side effects than the racemic
mixture (C. S. T. Aun, 1999, Br. J. Anaesthesia 83: 29-41). Studies
have shown that ketamine is converted metabolically through
demethylation to norketamine, in vivo, at rates dependent on the
route of administration, with oral and rectal administrations
having the fastest rates due to a high degree of first pass
metabolism in the liver (see, e.g., Grant et al., 1981, Br. J.
Anaesth. 53: 805-810; Grant et al., 1981, Br. J. Anaesth. 55:
1107-1111; Leung et al., 1985, J. Med. Chem. 29: 2396-2399;
Malinovsky et al., 1996, Br. J. Anaesthesia 77: 203-207).
Norketamine binds the NMDA receptor less tightly than either S- or
R-ketamine (Ebert et al., 1997, Eur. J. Pharm. 333: 99-104) and
norketamine is speculated to have an anesthetic and analgesic
potency one third that of ketamine (C. S. T. Aun, 1999, Br. J.
Anaesthesia 83: 29-41), perhaps explaining the absence of
administration of norketamine as an analgesic in the art.
[0004] Ketamine also has analgesic properties (Domino et al., 1965,
Clin. Pharmacol. Ther. 6:279); profound analgesia can be achieved
with subanesthetic doses of ketamine (Bovill, 1971, Br. J. Anaesth.
43:496; Sadove et al., 1971, Anesth. Analg. 50:452-457). The drug
is administered by various routes, including i.v., i.m., caudal,
intrathecal, oral, rectal, and subcutaneous (s.c.) (see, e.g.,
Oshima et al., 1990, Can. J. Anaesth. 37:385-386).
[0005] Management of pain, and particularly chronic pain, is
complex and frequently unsuccessful. The first line of treatment
usually involves administration of opioid agonists, e.g., narcotics
such as morphine (see, e.g., Anderson and Brill, 1992, Semin.
Anesth. 11: 158-171). However, rapid tolerance and marked
resistance to narcotics frequently develop, thus rendering these
agents ineffective (see, e.g., Abram, 1993, Reg. Anesth.
18(SUPPL):406-413). Non-competitive N-methyl-D-aspartate (NMDA)
receptor antagonists, such as ketamine and norketamine, have been
reported to interfere with the development of tolerance to the
analgesic effects of morphine, possibly through blockade of the
NMDA receptor rather than from "side-effects" of the antagonist,
since the antagonists were not found to reverse tolerance (Trujillo
and Akil, 1994, Brain Res. 633:178-188).
[0006] Often, pain management involves administration of a plethora
of drugs, such as narcotics, agonist-antagonist agents,
butorphanols, benzodiazepines, GABA stimulators, barbiturates,
barbiturate-like drugs, orally, e.g., in a pill or liquid
formulation, or by i.v. or i.m. injection. Opioid agonists and
antagonists may be combined. Thus, a combination of drugs can have
offsetting or compounding effects. More problematic is the
possibility of adverse side effects, particularly gastric distress
that accompanies oral administration, or the fear that injections
can inspire.
[0007] U.S. Pat. Nos. 5,543,434 and 6,248,789 B1 disclose
transmucosal and nasal administrations of ketamine for the
management of pain and to reduce drug dependency. Under the methods
of Weg, dosages must be kept low in order to avoid the dysphoric
side effects attributable to ketamine. However, studies have
indicated that norketamine, delivered intravenously (Leung et al.,
1985, J. Med. Chem. 29: 2396-2399) or intraspinally (Shimoyama et
al., 1999, Pain 81: 85-93) to rats, produced fewer of the adverse
sequelae than an equal dose of ketamine.
[0008] Thus, there is a need for pain management therapies, which
reduce the dose of analgesics, including the narcotics. This and
other needs in the art have been addressed by the instant
invention, which is based on a novel finding that S-norketamine,
R-norketamine, racemic mixtures thereof, and prodrugs thereof can
be used to alleviate pain safely and effectively in doses that
would have been sub-optimal or ineffective alone, but provide
analgesic relief when in combination with a narcotic. The invention
also provides a method of alleviating pain with administration of
norketamine and a narcotic in doses that would have been
sub-optimal or ineffective if administered alone, but provide
analgesic relief when in combination.
[0009] The citation or identification of any reference in this
application shall not be construed as an admission that such
reference is available as prior art to the present invention.
However, all references and citations identified in this
application are incorporated in their entirety by reference in the
present application.
SUMMARY OF THE INVENTION
[0010] The object of the present invention is to provide a drug
composition comprising racemic norketamine, (S)-norketamine,
(R)-norketamine, their respective salts, solvates, or prodrugs, or
any combinations thereof in combination with an opioid, provided
that the effective amount of the norketamine, if administered in
the absence of the opioid, would be insufficient to exert an
optimal analgesic effect on the subject. Prodrugs of norketamine
may be provided through the chemical linking of norketamine to a
variety of carboxylic acids and other substituents to afford the
formulae shown in Structures 1 and 2 below.
##STR00001##
and wherein R.sub.3 and R.sub.4 are phenyl, aryl, azaaryl, alkyl,
branched alkyl, cycloalkyl, alkenyl, cycloalkenyl; where
R.sub.5.dbd.OH or SH; and where R.sub.6=alkyl, branched alkyl;
racemic mixtures of compounds of formula 1 and formula 2 in which
R.sub.1.dbd.H and R.sub.2 can be any of the groups recited above,
including H; and pharmaceutically acceptable salts and solvates
thereof.
[0011] When R-norketamine is in the free base form, it has a (+)
optical rotation and when in the salt form a (-) optical rotation.
S-norketamine has a (-) optical rotation when in the free base form
and when in the salt form a (+) optical rotation.
[0012] As well, the invention provides a method of pain treatment
where the effective amount of the opioid, if administered in the
absence of a norketamine compound, would be insufficient to exert
its optimum analgesic effect on the subject. The norketamine
compound and the opioid ingredients may be administered separately
or concomitantly and synergistically contribute to achieve an
optimum analgesic effect.
[0013] Examples of opioids include, but are not limited to
fentanyl, sefentanil, alfentanil, morphine, hydromorphine,
oxymorphine, methadone, oxycodone, hydrocodone, remifentanil,
dihydrocodeine, ethylmorphine, nalbuphine, buprenorphine,
dihydromorphine, normorphine, dihydroetorphine, butorphanol,
pentazocine, phenazocine, codeine, meperidine, propoxyphene,
tramadol, levorphanol, L-acetylmethadol, diacetylmorphine (heroin),
etorphine, normethadone, noroxycodone, and norlevorphanol. In one
preferred embodiment, the opioid is morphine. Opioids are
understand by one of skill in the art to include their salt
forms.
[0014] In another embodiment of the present invention, a method of
inhibiting tolerance to a narcotic analgesic in a subject in need
thereof is provided, comprising co-administering to a subject in
need thereof (S)-norketamine, (R)-norketamine, their respective
salts, solvates, or prodrugs, or any combinations thereof with a
narcotic analgesic, in which the narcotic analgesic, if
administered in the absence of the (S)-norketamine,
(R)-norketamine, their respective salts, solvates, or prodrugs, or
any combinations thereof, would induce in the subject a tolerance
for the narcotic analgesic. The invention may also be effective
where the narcotic analgesic could induce in the subject a
tolerance for the narcotic analgesic after about one week of daily
administration.
[0015] Compositions of the present invention may be delivered by
any of a number of routes, including transdermal, nasal, rectal,
vaginal, oral, transmucosal, intravenous, intramuscular, caudal,
intrathecal, and subcutaneous. In a further embodiment, the present
invention provides for pulmonary administration by inhalation.
Transdermal, nasal, and pulmonary administration advantageously
allows for patient self administration of the drug, which provides
for pain management on an outpatient basis. Moreover,
administration in transdermal patches, nasal sprays, and inhalers
are generally socially acceptable.
[0016] In yet another embodiment of the invention, a device is
provided for patient self-administration of norketamine/opioid
compositions. The device of the invention may comprise a pulmonary
inhaler containing a formulation of norketamine/opioid
compositions, optionally with a pharmaceutically acceptable
dispersant, wherein the device is metered to disperse an amount of
the formulation that contains a dose of norketamine with narcotic
effective to alleviate pain. The dispersant may be a surfactant,
such as, but not limited to, polyoxyethylene fatty acid esters,
polyoxyethylene fatty acid alcohols, and polyeoxyethylene sorbitan
fatty acid esters.
[0017] In one specific embodiment, the formulation is a dry powder
formulation in which the norketamine/narcotic composition is
present as a finely divided powder. The dry powder formulation can
further comprise a bulking agent, such as, but not limited to,
lactose, sorbitol, sucrose and mannitol, or the norketamine/opioid
compositions may be associated with carrier particles.
[0018] In another specific embodiment, the formulation is a liquid
formulation, optionally comprising a pharmaceutically acceptable
diluent, such as, but not limited to, sterile water, saline,
buffered saline and dextrose solution.
[0019] In further embodiments, the formulation further comprises a
benzodiazepine in a concentration such that the metered amount of
the formulation dispersed by the device contains a dose of the
benzodiazepine effective to inhibit dysphoria, or a narcotic in a
concentration such that the metered amount of the formulation
dispersed by the device contains a dose of the narcotic effective
to alleviate pain.
[0020] There has thus been outlined, rather broadly, certain
embodiments of the invention in order that the detailed description
thereof herein may be better understood, and in order that the
present contribution to the art may be better appreciated. There
are, of course, additional embodiments of the invention that will
be described below and which will form the subject matter of the
claims appended hereto.
[0021] In this respect, before explaining at least one embodiment
of the invention in detail, it is to be understood that the
invention is not limited in its application to the details of
construction and to the arrangements of the components set forth in
the following description or illustrated in the drawings. The
invention is capable of embodiments in addition to those described
and of being practiced and carried out in various ways. Also, it is
to be understood that the phraseology and terminology employed
herein, as well as the abstract, are for the purpose of description
and should not be regarded as limiting.
[0022] As such, those skilled in the art will appreciate that the
conception upon which this disclosure is based may readily be
utilized as a basis for the designing of other structures, methods
and systems for carrying out the several purposes of the present
invention. It is important, therefore, that the claims be regarded
as including such equivalent constructions insofar as they do not
depart from the spirit and scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows norketamine in dose-dependent antinociception
in a rodent model of neuropathy (mechanical test).
[0024] FIG. 2 shows norketamine in dose-dependent antinociception
in a rodent model of neuropathy (thermal test).
[0025] FIG. 3 shows antinocipentive efficacy of norketamine vs.
ketamine.
[0026] FIG. 4 shows antinocipentive efficacy of S-norketamine.
[0027] FIG. 5 shows antinocipentive efficacy of R-norketamine.
[0028] FIG. 6 compares antinocipentive efficacy of S- and
R-norketamine.
[0029] FIG. 7 shows the correlation between antinocipentive
efficacy of norketamine vs. its plasma levels.
[0030] FIG. 8 shows the affect of norketamine on motor
function.
[0031] FIG. 9 shows the affect of norketamine to induce ataxia.
[0032] FIG. 10 shows the synergistic analgesic effect of morphine
with racemic norketamine following IP administration.
[0033] FIG. 11 shows the synergistic analgesic effect of morphine
with S-norketamine following IP administration. From left to right
the bars represent S-norketamine, 3 mg/kg, morphine 3 mg/kg, and
S-norketamine, 3 mg/kg with morphine 3 mg/kg.
[0034] FIG. 12 shows the synergistic analgesic effect of morphine
with S-norketamine following intrathecal administration. From left
to right the bars represent S-norketamine 100 mcg (n=7), morphine
0.5 mcg (n=4) and S-norketamine 100 mcg with morphine 0.5 mcg
(n=6).
[0035] FIG. 13 shows the reduction of morphine tolerance with
S-norketamine administration.
[0036] FIG. 14 shows the analgesic effect of morphine after IP
administration.
[0037] FIG. 15 shows the analgesic effect of morphine after IT
administration.
[0038] FIG. 16 shows the effect of S-norketamine alone after IP and
IT administration.
[0039] FIG. 17 shows the synergistic effect of morphine by
S-norketamine after IP administration.
[0040] FIG. 18 shows the synergistic effect of morphine by
S-norketamine after IT administration.
[0041] FIG. 19 also shows the synergistic effect of S-norketamine
and oxycodone.
[0042] FIG. 20 shows that tolerance of oxycodone is inhibited by
S-norketamine.
[0043] FIG. 21 shows the synergistic effect of S-norketamine and
morphine
DETAILED DESCRIPTION OF THE INVENTION
[0044] The present invention relates to the administration of
norketamine and a narcotic in combination for the treatment of
pain. More specifically, the present invention provides
administration of sub-analgesic doses of norketamine and/or the
narcotic, which, when used in combination, provides an analgesic
effect. The invention also provides a method and device for patient
self administration of the described drugs for pain management.
[0045] The present invention contemplates the use of racemic or
enantiomericaly pure compositions of norketamine. S- and
R-norketamine are described by formulae 1 and 2 [below],
respectively, wherein R.sub.1 and R.sub.2 are hydrogen. While the
invention will be
##STR00002##
described, in significant part, with reference to "norketamine,"
analgesic compositions described herein may also comprise prodrugs
(i.e., derivatives) of norketamine as described in detail in U.S.
Patent Application Publication No. 20040248964, filed on Nov. 18,
2003, the disclosure of which is incorporated herein in its
entirety by reference. Thus, unless more specific language is
recited, the term "norketamine" is used herein to encompass the
individual isomers of norketamine and derivatives thereof.
[0046] In specific embodiments, norketamine refers to salts of
norketamine, such as norketamine hydrochloride. There is no
limitation on the nature of these salts, provided that, when used
for therapeutic purposes, they are pharmaceutically acceptable,
which, as is well-known in the art, means that they do not have
reduced activity or increased toxicity compared with the free
compounds. Examples of these salts include: salts with an inorganic
acid such as hydrochloric acid, hydrobromic acid, hydriodic acid,
nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and
salts with an organic acid, such as methanesulfonic acid,
trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic
acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic
acid, citric acid, succinic acid, tartaric acid; and other mineral
and carboxylic acids well known to those skilled in the art.
Examples of salts with inorganic cations such as sodium, potassium,
calcium, magnesium, lithium, aluminum, zinc, etc; and salts formed
with pharmaceutically acceptable amines such as ammonia,
alkylamines, hydroxyalkylamines, lysine, arginine,
N-methylglucamine, procaine and the like.
[0047] "Prodrugs of norketamine" is used herein to refer to all
compounds that may be converted physiologically to norketamine.
While it is well known that ketamine is metabolized to norketamine
in vivo, it is important to note that ketamine is not to be
considered a prodrug of norketamine, and the term "norketamine
prodrug" in all its forms specifically excludes ketamine as used in
this application.
[0048] Prodrugs of norketamine may be provided through the chemical
linking of norketamine to a variety of carboxylic acids and other
substituents to afford the formulae shown in Structures 1 and 2
below.
##STR00003##
wherein:
R.sub.1=Methyl, R.sub.2.dbd.CH.sub.2OCOR.sub.3
R.sub.1.dbd.H, R.sub.2.dbd.CH.sub.2OCOR.sub.3
R.sub.1=Methyl, R.sub.2.dbd.CH.sub.2COOR.sub.3
R.sub.1.dbd.H, R.sub.2.dbd.CH.sub.2COOR.sub.3
R.sub.1=Methyl, R.sub.2.dbd.COOR.sub.3
R.sub.1.dbd.H, R.sub.2.dbd.COOR.sub.3
R.sub.1=Methyl,
R.sub.2.dbd.COOCH.sub.2CH.sub.2N(CH.sub.3).sub.2
R.sub.1.dbd.H, R.sub.2.dbd.COOCH.sub.2CH.sub.2N(CH.sub.3).sub.2
R.sub.1=Methyl, R.sub.2.dbd.COOCH(R.sub.3)OCOR.sub.4
R.sub.1.dbd.H, R.sub.2.dbd.COOCH(R.sub.3)OCOR.sub.4
##STR00004## ##STR00005##
[0049] and wherein R.sub.3 and R.sub.4 are phenyl, aryl, azaaryl,
alkyl, branched alkyl, cycloalkyl, alkenyl, cycloalkenyl; where
R.sub.5.dbd.OH or SH; and where R.sub.6=alkyl, branched alkyl;
racemic mixtures of compounds of formula 1 and formula 2 in which
R.sub.1.dbd.H and R.sub.2 can be any of the groups recited above,
including H; and pharmaceutically acceptable salts and solvates
thereof. Aryl, azaaryl, alkyl, branched alkyl, cycloalkyl, alkenyl,
cycloalkenyl moieties can be C.sub.1-C.sub.6.
[0050] "Narcotics" are defined herein as opioids and
interchangeably used. Narcotics and opiods are ligands that bind to
the mu, delta and kappa receptors. Narcotics suitable in the
present invention, include, but are not limited to, fentanyl,
sefentanil, alfentanil, morphine, hydromorphine, oxymorphine,
methadone, oxycodone, hydrocodone, remifentanil, dihydrocodeine,
ethylmorphine, nalbuphine, buprenorphine, dihydromorphine,
normorphine, dihydroetorphine, butorphanol, pentazocine,
phenazocine, codeine, meperidine, propoxyphene, tramadol,
levorphanol, L-acetylmethadol, diacetylmorphine (heroin),
etorphine, normethadone, noroxycodone, and norlevorphanol. Morphine
is a preferred narcotic in some embodiments of the invention.
Narcotics of the present invention can be in salt form. Also,
narcotics of the present invention can be in prodrug form.
Exemplary prodrugs include the prodrug forms described above for
norketamine.
[0051] An "optimal" dose is defined as a dose of an analgesic, when
taken alone, is sufficient to provide analgesic relief. In the rat,
for example, an optimal dose of norketamine is about 8 mg/kg
intraperitoneally (IP). A "sub-optimal" dose is defined as about 1
to about 60% of the optimal dose used to induce analgesia; more
preferably about 5% to about 40%, and even more preferably about
10% to about 20%. A "sub-analgesic" does is defined as a dose at
which little to no analgesic effect is provided. For example, a
sub-analgesic dose of norketamine is less than about 3 mg/kg.
Typically, a sub-analgesic dose correlates with less than about 5
AUC units or less than about 5% MPE (maximum possible effect).
[0052] The actual dose will vary, of course, depending on the body
weight of the patient, the severity of the pain, the route of
administration, such as oral verses a parenteral route, the nature
of medications administered concurrently, the number of doses to be
administered per day, and other factors generally considered by the
ordinary skilled physician in the administration of drugs.
Exemplary dosage ranges are 0.05 to 500 mg/kg, more preferably 0.5
to 50 mg kg. Exemplary ratios of opioid to norketamine or 0.05 to
50:1, more preferably 0.1 to 10:1.
[0053] As well, the apparent dose for analgesia will often depend
on the test model used. Protocols for determining optimal analgesic
doses of a given drug in pain management in animal models are known
in the art.
[0054] One of these protocols will now be described with respect to
the invention.
Tail-Flick Test
[0055] A dose response curve was generated by determining the
analgesic effects of combining a constant dose of an opioid (e.g.,
morphine) along with an increasing dose of R,S-norketamine, Male
and female Sprague-Dawley rats (n=8/sex) all with an approximate
age of 85 to 90 days. Each rat should be weighed, prior to being
subjected to any tests, on the day of the experiment. Experiments
were performed in 72 hour intervals, and prior to the test, the
rats were habituated for three days to handling and the tail-flick
procedure without heat exposure. [0056] 1 The tail-flick apparatus
(IITC Model 33, Life Science, Woodland Hills, Calif.) is pre-warmed
for at least 30 minutes. [0057] 2 The intensity of the lamp is
adjusted so that baseline tail-flick latency for the rats is equal
to approximately 2.0 seconds. In the present experiment, the
intensity was set to 40% as this was determined to be the ideal
intensity from the intensity response curve. [0058] 3 The
tail-flick apparatus is preferably programmed to use a cut off
point of 10 seconds to prevent tissue damage to the rats in the
case that the tail does not flick. [0059] 4 A rat is placed in a
mitten and its tail blackened with ink approximately 2 inches in
length at 1 inch from the base of the tail. [0060] 5 The tail is
then placed flatly in the groove of the tail-flick apparatus.
[0061] 6 Once heat exposure is initiated, the lamp is set to turn
off automatically when the tail moves from the heat source. [0062]
7 For each rat, a baseline score is determined prior to injection.
Tail-flick latency ("TFL") is measured twice in an approximate 15
minute intervals and an average of the two times determines the
baseline. [0063] 8 Once the baseline value is determined, TFL is
measured, following the injection of drugs, at times 15, 30, 60 and
120 minutes.
Solutions:
[0063] [0064] 9 Morphine: 3 mg/kg [0065] injection volume of 0.5
ml/kg: makeup solution of 6 mg/ml saline. [0066] For 8 rats 24 mg
of morphine should be mixed with 4 ml of saline to give the proper
amount of drug needed for a 3 mg/kg dose at an injection volume of
0.5 ml/kg. [0067] 10 Norketamine: 3 mg/kg, 1-5 mg/kg, 0.75 mg/kg:
injection volume of 0.5 ml/kg: make up solution of 6 mg/ml saline:
Method for preparing proper amount of drugs to be used for 8 rats.
[0068] 3 mg/kg (A). Mix 12 mg R,S-norketamine with 2 ml saline to
give a 6 mg/ml solution to be given at an injection volume of 0.5
ml/kg. Dilute original (A) solution to obtain the following
concentrations: [0069] 1.5 mg/kg (B): take 1 ml of (A) and dilute
with 1 ml of saline [0070] 0.75 mg/kg (C): take 1 ml of (B) and
dilute with 1 ml of saline [0071] 11 Saline solution (control):
(D)
Drug Administration (I.P.):
Total volume (mL) injected is equal to body weight (kg). Each
animal is given an injection of morphine that is 0.5 ml/kg body
weight, and an injection of norketamine or control that is 0.5
ml/kg body weight.
[0072] Example: body weight=250 g=0.25 kg=0.25 ml
[0073] For each drug to be injected: 0.5 ml/kg.times.0.250 kg=0.125
ml injected
Calculations:
[0074] Normalize data for baseline value (postinjection value at
each time point-average preinjection baseline). [0075] Calculate
area under the curve (AUC.sub.0-120min) for normalized data. [0076]
Calculate maximum area under the curve (AUC.sub.max), assuming 10
second response for each time point. [0077] Calculate %
MPE=(AUC.sub.0-120min)/(AUC.sub.max).times.100. [0078]
Post-injection thresholds are compared to the baseline threshold
using paired t-test. [0079] The difference between doses will be
analyzed by 2 way RM ANOVA. [0080] The difference between sex will
be analyzed by 2 way RM ANOVA. [0081] All data are presented as
mean .+-.SEM of n rats.
Method of Calculations:
[0081] [0082] Normalized data (NOR): subtract average baseline from
each value NOR=(post-injection TFL)-(pre-injection baseline) [0083]
12 Percent maximum effect (MPE): [0084] % MPE=(post-injection
value-pre-injection baseline)/(cut-off-pre-injection
baseline).times.100% [0085] 13 Area under the time action curve
(AUC.sub.0-120 min) calculated by trapezoidal rule [0086]
Individual AUC.sub.0-120 min.=(average value over the time
interval).times.(time interval) [0087] Total AUC.sub.0-120 min.:
sum of individual AUC [0088] Example: AUC.sub.0-120 min., %
MPE=(15-0
min).times.[(MPE0+MPE15).times.1/2]+(30-15).times.[(MPE30+MPE15).times.1/-
2]
Graphs:
[0088] [0089] Time action curves were plotted for each dose [0090]
Plot data v. concentration for both maximum % MPE and AUC.sub.0-120
min were plotted. (FIGS. 10-14).
[0091] The invention may be used to alleviate pain from many
causes, including but not limited to shock; limb amputation; severe
chemical or thermal burn injury; sprains, ligament tears,
fractures, wounds and other tissue injuries; dental surgery,
procedures and maladies; labor and delivery; during physical
therapy; post operative pain; radiation poisoning; cancer; acquired
immunodeficiency syndrome (AIDS); epidural (or peridural) fibrosis;
failed back surgery and failed laminectomy; sciatica; painful
sickle cell crisis; arthritis; autoimmune disease; intractable
bladder pain; and the like. Administration of norketamine/narcotic
combination is also amenable to hospice use, particularly hospices
that specialize in the care of cancer and AIDS patients.
[0092] The invention also provides self-management of pain on an
outpatient basis comprising administering via conventional routes,
including transdermal, nasal, rectal, vaginal, oral, transmucosal,
intravenous, intramuscular, intrathecal, epidural, subcutaneous,
and other routes, of norketamine with narcotics effective to
alleviate pain to a subject suffering from pain. Uses of
norketamine/narcotic drugs would also apply, for example, to
treating headaches, drug abuse, mood and anxiety disorders, as well
as other neuropsychiatric disorders, both motoric and cognitive,
such as Alzheimer's disease, Parkinson's syndrome, Restless Leg
Syndrome which are thought to be caused by neurodegeneration.
[0093] In one embodiment, administration of norketamine with
narcotic drugs may relieve or alleviate episodes of acute
breakthrough pain or pain related to wind-up that can occur in a
chronic pain condition. In a further embodiment, administration of
norketamine/narcotic compositions may be used as an adjunct therapy
to a conventional treatment regimen for a chronic pain condition to
alleviate breakthrough pain or pain related to wind-up.
[0094] The norketamine/opioid compositions will preferably be
prepared in a formulation or pharmaceutical composition appropriate
for administration by the transmucosal route, e.g., nasal,
transbuccal, sublingual, vaginal, and rectal; by the oral route
(via the gastrointestinal tract, rather than the oral-pharyngeal
mucosa); by the pulmonary route (i.e., inhaled); or by the
parenteral route, e.g., intravenous, intraarterial,
intraperitoneal, intradermal, intramuscular, intraventricular, or
subcutaneous. Suitable formulations are discussed in detail, infra.
In a further embodiment, the norketamine/narcotic composition can
be formulated with a mucosal penetration enhancer to facilitate
delivery of the drug. The formulation can also be prepared with pH
optimized for solubility, drug stability, absorption through skin
or mucosa, and other considerations.
[0095] In another embodiment, the dose of norketamine and narcotic,
individually, is about 0.01 mg per kg of body weight (0.01 mg/kg)
to about 200 mg/kg; preferably about 0.05 mg/kg to about 80 mg/kg,
more preferably 1 mg/kg to about 50 mg/kg. In yet another
embodiment, the dose ranges from about 1 mg to about 30 mg.
Preferably, the effective dose is titrated under the supervision of
a physician or medical care provider so that the optimum dose for
the particular application is accurately determined. Thus, the
present invention provides a dose suited to each individual
patient.
[0096] Once the dosage range is established, a further advantage of
the invention is that the patient can administer the norketamine
with narcotic on an as-needed, dose-to-effect basis. Thus, the
frequency of administration is under control of the patient.
However, the relatively low dose with each administration will
reduce the possibilities for abuse that arise under patient
self-administration.
[0097] Yet another particular advantage of the present invention is
that transmucosal or pulmonary administration of the norketamine
with narcotic is non-invasive, and provides for introduction into
the bloodstream almost as fast as i.v. administration, and much
faster than perioral administration.
[0098] More importantly, a patient can control administration of
the pain medication, because transmucosal or pulmonary
administration provides for precise control over the dosage and
effect of the drug used to offset changes in activity and pain
levels throughout a day. Transmucosal or pulmonary administration
of the norketamine/opioid compositions optimally provides for
dose-to-effect administration of the drug. Transdermal
administration, though not as fast acting, similarly allows for
precise control of the dosage and also provides for excellent
dose-to-effect administration of the drug.
[0099] Thus, according to the invention, the patient can safely
administer an amount of drug effective to alleviate pain by
controlling the amount and frequency of administration of a
formulation according to the invention. Safe patient regulated
control of pain medication is an important advantage because pain
is such a subjective condition. The advantage is two-fold here, as
the patient can effectively alleviate pain, and the power to
alleviate the pain will have significant psychological benefits. A
positive psychological attitude can significantly improve the
course and outcome of a treatment regimen, as well as making the
entire process more bearable to the patient.
[0100] The term "breakthrough pain" is used herein in accordance
with its usual meaning in pain treatment. For example, breakthrough
pain can refer to pain experienced by a subject receiving treatment
for pain, but who experiences a level of pain that is not treatable
by the current treatment regimen. "Spike pain" is an acute form of
breakthrough pain: Usually medications or therapies for chronic
pain do not provide adequate relief for breakthrough pain, either
because the maximum pain relief effects of these regimens have been
achieved, because of tolerance to medications that has developed,
or because the treatment is not fast enough. Pain related to "wind
up" is that pain arising from repeated stimuli which causes a
temporal summation of C-fiber-mediated responses of dorsal horn
nociceptive neurons and that may be expressed physically as
hyperalgesia (increased pain sensation) and allodynia (pain arising
from a stimulus that is not normally painful).
[0101] A subject in whom administration of norketamine/opioid
compositions is an effective therapeutic regimen for management of
pain, or for synergism with alternative pain therapy is preferably
a human, but can be any animal. Thus, as can be readily appreciated
by one of ordinary skill in the art, the methods and devices of the
present invention are particularly suited to administration of
norketamine/opioid compositions to any animal, particularly a
mammal, and including, but by no means limited to, domestic
animals, such as feline or canine subjects, farm animals, such as
but not limited to bovine, equine, caprine, ovine, and porcine
subjects, wild animals (whether in the wild or in a zoological
garden), research animals, such as mice, rats, rabbits, goats,
sheep, pigs, dogs, cats, etc., i.e., for veterinary medical use.
For veterinary use, rectal administration or transdermal
administration are convenient and allow for minimal aggravation or
irritation of the animal.
[0102] The term "mucosal" refers to a tissue comprising a mucous
membranes, such as the oral, buccal, rectal, or vaginal mucosa and
the pulmonary mucosa. "Transmucosal" refers to administration of a
drug through the mucosa to the bloodstream for systemic delivery of
the drug. One distinct advantage of transmucosal delivery is that
it provides delivery of drug into the bloodstream almost as fast as
parenteral delivery, but without the unpleasant necessity of
injection.
[0103] The term "transdermal administration" in all its grammatical
forms refers to administration of a drug through the dermis to the
bloodstream for systemic delivery of the drug. The advantages of
transdermal administration for drug delivery are that it does not
require injection using a syringe and needle, it avoids necrosis
that can accompany i.m. administration of drugs, it avoids the need
to constantly suck on a lollipop, and transdermal administration of
a drug is highly amenable to self administration.
[0104] "Pulmonary administration" refers to administration of a
drug through the pulmonary tract (i.e., inhaled into the lungs) to
the bloodstream for systemic delivery of the drug. The present
invention contemplates pulmonary administration through an inhaler
in a particular aspect.
[0105] The term "mucosal penetration enhancer" refers to a reagent
that increases the rate or facility of transmucosal penetration of
norketamine or a ketamine/norketamine prodrug, such as but not
limited to, a bile salt, fatty acid, surfactant or alcohol. In
specific embodiments, the permeation enhancer can be sodium
cholate, sodium dodecyl sulphate, sodium deoxycholate,
taurodeoxycholate, sodium glycocholate, dimethylsulfoxide or
ethanol.
[0106] A "therapeutically effective amount" of a drug is an amount
effective to demonstrate a desired activity of the drug. According
to the instant invention, a therapeutically effective amount of a
norketamine with narcotic is an amount effective to alleviate,
i.e., noticeably reduce, pain in a patient.
[0107] The invention will now be described in greater detail, with
particular reference to transdermal, transmucosal, and pulmonary
administration of the norketamine/opioid compositions and
additional therapeutically active drugs or agents with which the
norketamine/opioid compositions can be administered.
Pulmonary and Nasal Transmucosal Administration of Norketamine and
Narcotic
[0108] The present invention contemplates formulations comprising
norketamine/opioid compositions for use in a wide variety of
devices that are designed for the delivery of pharmaceutical
compositions and therapeutic formulations to the respiratory tract,
preferably the pulmonary and bronchial passages. A preferred route
of administration of the present invention is in an aerosol spray
for pulmonary inhalation. Norketamine/opioid compositions,
optionally combined with a dispersing agent, or dispersant, can be
administered in an pulmonary formulation as a dry powder or in a
solution or suspension, optionally with a diluent.
[0109] As used herein, the term "aerosol" refers to suspension in
the air. In particular, aerosol refers to the particalization or
atomization of a formulation of the invention and its suspension in
the air. According to the present invention, a pulmonary
formulation is a formulation comprising a norketamine/opioid
compositions for inhalation or pulmonary administration.
[0110] As used herein, the term "inhaler" refers both to devices
for nasal-transmucosal and pulmonary administration of a drug,
e.g., in solution, powder and the like. For example, the term
"inhaler" is intended to encompass a propellant driven inhaler or a
dry powder inhaler, such as is used for to administer antihistamine
for acute asthma attacks, and plastic spray bottles, such as are
used to administer decongestants. As used herein, "inhaler" will
also encompass the term "nebulizer" as it is well known in the
art.
[0111] As used herein, the term "dispersant" refers to an agent
that assists aerosolization or absorption of the norketamine/opioid
compositions in mucosal tissue, or both. In a specific aspect, the
dispersant can be a mucosal penetration enhancer. Preferably, the
dispersant is pharmaceutically acceptable. As used herein, the term
"pharmaceutically acceptable" means approved by a regulatory agency
of the Federal or a state government or listed in the U.S.
Pharmacopeia or other generally recognized pharmacopeia for use in
animals, and more particularly in humans.
[0112] Suitable dispersing agents are well known in the art, and
include but are not limited to surfactants and the like. For
example, surfactants that are generally used in the art to reduce
surface induced aggregation of norketamine or a
ketamine/norketamine prodrug caused by atomization of the solution
forming the liquid aerosol may be used. Nonlimiting examples of
such surfactants are surfactants such as polyoxyethylene fatty acid
esters and alcohols, and polyoxyethylene sorbitan fatty acid
esters. Amounts of surfactants used will vary, being generally
within the range or 0.001 and 4% by weight of the formulation.
Suitable surfactants are well known in the art, and can be selected
on the basis of desired properties, depending on the specific
formulation, concentration of norketamine and narcotic, diluent (in
a liquid formulation) or form of powder (in a dry powder
formulation), etc.
[0113] The liquid formulations contain norketamine/opioid
compositions, optionally with a dispersing agent, in a
physiologically acceptable diluent. The dry powder formulations of
the present invention consist of a finely divided solid form of
norketamine/opioid compositions, optionally with a dispersing
agent. With either the liquid or dry powder formulation, the
formulation must be aerosolized. That is, it must be broken down
into liquid or solid particles in order to ensure that the
aerosolized dose actually reaches the mucous membranes of the
bronchial passages or the lungs. The term "aerosol particle" is
used herein to describe the liquid or solid particle suitable for
transmucosal or pulmonary administration, i.e., that will reach the
mucous, membranes or lungs. Other considerations, such as
construction of the delivery device, additional components in the
formulation, and particle composition and characteristics are
important. These aspects of transmucosal or pulmonary
administration of a drug are well known in the art, and
manipulation of formulations, aerosolization means, and
construction of a delivery device require, at most, routine
experimentation by one of ordinary skill in the art.
[0114] For nasal or pulmonary administration, a useful device is a
small, hard bottle to which a metered dose sprayer is attached. In
one embodiment, the metered dose is delivered by drawing the
norketamine and/or ketamine/norketamine prodrug solution into a
chamber of defined volume, which chamber has an aperture
dimensioned to aerosolize the formulation by forming a spray when a
liquid in the chamber is compressed. The chamber is compressed to
administer the norketamine and narcotic. In a specific embodiment,
the chamber is a piston arrangement. Such devices are commercially
available.
[0115] Alternatively, a plastic squeeze bottle with an aperture or
opening dimensioned to aerosolize an pulmonary formulation by
forming a spray when squeezed. The opening is usually found in the
top of the bottle, and the top is generally tapered to partially
fit in the nasal passages for efficient administration of the
aerosol formulation. Preferably, the nasal or pulmonary inhaler
will provide a metered amount of the formulation, for
administration of a measured dose of the drug.
[0116] Often, the aerosolization of a liquid or a dry powder
formulation for inhalation into the lung will require a propellent.
The propellent may be any propellant generally used in the art.
Specific nonlimiting examples of such useful propellants are a
chlorofluorocarbon, a hydrofluorocarbon, a hydrochlorofluorocarbon,
or a hydrocarbon, including trifluoromethane,
dichlorodifluoromethane, dichlorotetrafluoroethanol, and
1,1,1,2-tetrafluoroethane, or combinations thereof.
[0117] Systems of aerosol delivery, such as the pressurized metered
dose inhaler and the dry powder inhaler are disclosed in Newman, S.
P., Aerosols and the Lung, Clarke, S. W. and Davia, D. editors, pp.
197-222, and in U.S. Pat. Nos. 6,358,530, 6,360,743, 6,406,745,
6,423,683, 6,565,888, and 6,630,169, the disclosures of which are
incorporated herein in their entireties, and can be used in
connection with the present invention.
[0118] In a further embodiment, as discussed in detail infra, a
nasal transmucosal or pulmonary formulation of the present
invention can include other therapeutically or pharmacologically
active ingredients in addition to norketamine/opioid compositions,
such as but not limited to a benzodiazepine or a narcotic
analgesic.
[0119] With regard to construction of the delivery device, any form
of aerosolization known in the art, including but not limited to
spray bottles, nebulization, atomization or pump aerosolization of
a liquid formulation, and aerosolization of a dry powder
formulation, can be used in the practice of the invention.
[0120] As noted above, in a preferred aspect of the invention, the
device for aerosolization is a metered dose inhaler. A metered dose
inhaler provides a specific dosage when administered, rather than a
variable dose depending on administration. Such a metered dose
inhaler can be used with either a liquid or a dry powder
formulation. Metered dose inhalers are well known in the art.
Transmucosal Administration
[0121] As noted above, the present invention is directed inter alia
to transmucosal administration of norketamine with an opioid.
Initial studies demonstrate that nasal administration of the drugs,
either via the nasal mucosa or pulmonary inhalation and absorption
via pulmonary mucosa, is highly effective for the treatment of
pain. Subsequently, it has been discovered that other routes of
transmucosal administration of the drug combinations are also
effective for treatment of pain, as set forth above. In particular,
it has surprisingly been discovered that transmucosal
administration of the drugs allows for effective pharmacokinetics
with low doses of the drug, thus avoiding dysphoria or other side
effects associated with bolus i.v. or i.m. dosing. Transmucosal
norketamine with narcotic is particularly indicated for
breakthrough and spike pain, e.g., as described in greater detail
above.
[0122] According to the invention, any transmucosal route of
administration, including but not limited to rectal, oral, vaginal,
buccal, etc. can be employed. In particular, the present invention
is directed to the following transmucosal routes of administration.
It can be readily appreciated that any of the transmucosal routes
of administration may be enhanced by use of a mucosal penetration
enhancer, e.g., as described supra. The selection of a particular
mucosal penetration enhancer may depend on the characteristics of
the specific mucosa. These factors are addressed in greater detail
below.
Administration Via Suppositories
[0123] In another aspect, norketamine and narcotic are formulated
in a matrix suitable for rectal (or vaginal) insertion, i.e., in a
suppository. The invention is not limited to any particular
suppository formulation. Indeed, many suppository formulations are
known in the art, e.g., as described in Remington's Pharmaceutical
Sciences, Physician's Desk Reference, and U.S. Pharmacopeia.
Administration via suppositories may be preferred in certain
situations, e.g., because convention and custom prefers it, or
where nasal administration is deemed unacceptable.
Administration Via Buccal Patch
[0124] According to the invention, norketamine and an opioid can be
formulated in a buccal patch for administration via the interior of
the cheek. It may be appreciated that a buccal patch constitutes
another form of transmucosal administration. The technology for
preparing buccal patch formulations is known in the art, e.g.,
Remington's Pharmaceutical Sciences, supra.
Oral-Pharyngeal Administration
[0125] In yet another embodiment, the norketamine and opioid can be
formulated for oral-pharyngeal, including sublingual and
transbuccal, administration. For example, norketamine/opioid
compositions can be incorporated in a "candy" matrix, such as that
described in U.S. Pat. No. 4,671,953, in a gum base, or a lozenge.
In another embodiment, the norketamine/opioid compositions can be
formulated in a capsule or pill form for sublingual placement.
[0126] It is particularly contemplated that norketamine/opioid
compositions for oral-pharyngeal administration may be formulated
with a flavor masking agent or coating. Many flavor masking agents
for use with oral pharmaceuticals are known in the art and can be
selected for use with the present invention.
Oral Administration
[0127] In still a further embodiment, the norketamine and opioid be
formulated for oral administration via the stomach and intestinal
mucosa. For oral administration, the drug can be administered in a
carrier designed for drug release in either the stomach (an 43
acidic environment), or the intestines, or both. Many capsules,
pills, and matrices for oral administration of a drug are known in
the art, and can be selected on the basis of compatibility with
norketamine and narcotic and the desired point and rate of drug
release by the ordinary skilled physician. Sustained release
formulations are preferred. One of skill in the art will appreciate
that dosages for oral administration are generally higher than
dosages administered by a parenteral route.
Transdermal Administration
[0128] In a further embodiment, as noted above, the present
invention is directed to transdermal administration of norketamine
with a narcotic. It has been discovered that transdermal
administration is also effective for treatment of pain, as set
forth above, for many of the same reasons transmucosal
administration is effective. In particular, it has surprisingly
been discovered that transdermal administration of norketamine and
opioid compositions allows for effective pharmacokinetics with low
doses of the drug, thus avoiding dysphoria or other side effects
associated with bolus i.v. or i.m. dosing. Transdermal
administration is particularly indicated for breakthrough and spike
pain, e.g., as described in greater detail above.
[0129] Various and numerous methods are known in the art for
transdermal administration of a drug, e.g., via a transdermal
patch. These methods and associated devices provide for control of
the rate and quantity of administration of a drug, and some allow
for continuous modulation of drug delivery. Transdermal patches are
described in, for example, U.S. Pat. No. 5,407,713, issued Apr. 18,
1995 to Rolando et al.; U.S. Pat. No. 5,352,456, issued Oct. 4,
1004 to Fallon et al; U.S. Pat. No. 5,332,213 issued Aug. 9, 1994
to D'Angelo et al; U.S. Pat. No. 5,336,168, issued Aug. 9, 1994 to
Sibalis; U.S. Pat. No. 5,290,561, issued Mar. 1, 1994 to Farhadieh
et al.; U.S. Pat. No. 5,254,346, issued Oct. 19, 1993 to Tucker et
al.; U.S. Pat. No. 5,164,189, issued Nov. 17, 1992 to Berger et al;
U.S. Pat. No. 5,163,899, issued Nov. 17, 1992 to Sibalis; U.S. Pat.
Nos. 5,088,977 and 5,087,240, both issued Feb. 18, 1992 to Sibalis;
U.S. Pat. No. 5,008,110, issued Apr. 16, 1991 to Benecke et al; and
U.S. Pat. No. 4,921,475, issued May 1, 1990 to Sibalis, the
disclosure of each of which is incorporated herein by reference in
its entirety.
[0130] It can be readily appreciated that a transdermal route of
administration may be enhanced by use of a dermal penetration
enhancer, e.g., such as enhancers described in U.S. Pat. No.
5,164,189 (supra), U.S. Pat. No. 5,008,110 (supra), and U.S. Pat.
No. 4,879,119, issued Nov. 7, 1989 to Aruga et al., the disclosure
of each of which is incorporated herein by reference in its
entirety.
[0131] In another embodiment, the norketamine/opioid compositions
can be delivered in a vesicle, in particular a liposome (see
Langer, 1990, Science 249:1527-1533; Treat et al, 1989, in
Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Berestein and Fidler (eds.), Liss: New York, pp. 353-365;
Lopez-Berestein, ibid, pp. 317-327; see generally ibid). To reduce
its systemic side effects, this may be a preferred method for
introducing norketamine/opioid compositions.
[0132] In yet another embodiment, norketamine and opioid may be
delivered in a controlled release system. For example, the drugs
may be administered using intravenous infusion, an implantable
osmotic pump, a transdermal patch, liposomes, or other modes of
sustained release administration. In one embodiment, a pump may be
used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.
14:201; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989,
N. Engl. J. Med. 321:574). In another embodiment, polymeric
materials can be used (see Medical Applications of Controlled
Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla.
(1974); Controlled Drug Bioavailability, Drug Product Design and
Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger
and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see
also Levy et al., 1985, Science 228:190; During et al., 1989, Ann.
Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). Other
controlled release systems are discussed in the review by Langer
(1990, Science 249:1527-1533).
Additional Therapeutically Active Drugs or Agents
[0133] As note above, the invention contemplates coordinate
administration of norketamine with an opioid, preferably, morphine.
The invention provides a method of alleviating pain by the
administration of both norketamine with an opioid where the dose of
the norketamine, alone, would have been sub-optimal for pain
treatment. As well, in a more preferred embodiment, invention
provides a method of alleviating pain by the administration of both
norketamine with an opioid where the dose of the opioid, alone,
would have been sub-optimal for pain treatment. The invention takes
advantage of the discovery that use of otherwise sub-optimal doses
of norketamine works synergistically with a narcotic, in
combination, to boost the analgesic effect of the combined therapy.
However, other drug(s) may be used in addition to the described
compositions.
[0134] For example, co-administration of the norketamine/opioid
compositions with a benzodiazepine is indicated to counteract the
potential dysphoric or hallucinogenic effects of high dose
administration of norketamine/opioid compositions. Thus, a
therapeutically effective amount of a benzodiazepine is an amount
effective to inhibit dysphoria. In a further embodiment, an amount
of a benzodiazepine also effective to sedate the patient may be
administered.
[0135] The mild adverse effects of ketamine, e.g., dysphoria and/or
hallucinations, sometimes called "ketamine dreams," can occur upon
administration of a dose of greater than 50 mg of ketamine, but
usually require doses greater than 100 mg per kg of ketamine. One
advantage of the present invention is that delivery of
norketamine/opioid compositions allows for control of the dose to a
level effective for analgesia, but below the level that results in
dysphoria. Another is that norketamine/opioid compositions are less
prone to adverse psychological effects than ketamine alone.
However, it is possible that an individual may overdose,
particularly in response to an acute episode of pain. Thus,
co-administration of a benzodiazepine may be indicated in certain
circumstances.
[0136] Benzodiazepines that may be administered according to the
present invention include, but are not limited to, flurazepam
(Dalmane), diazepam (Valium), and, preferably, Versed. In a
preferred aspect, the transmucosal formulation of the invention
comprises ketamine and a benzodiazepine, each present in a
therapeutically effective amount.
[0137] Where medical necessity or preference dictates, parenteral
administration of norketamine/opioid compositions can be effected
to synergistically treat pain with other pain therapies. Alternate
pain therapies include non-pharmaceutical treatments, such as but
not limited to, chiropractic medicine, acupuncture, biofeedback,
and other alternative therapies.
[0138] Preferably, the synergistic effects of norketamine and
narcotic administration are reflected by reduced dependency on
other pain therapies, or by an reduction in the level of pain
experienced, or both. This aspect of the invention is based on the
surprising discovery administration of norketamine/opioid
compositions allow for a reduction over time of narcotic
analgesics. Such a reduction over time runs counter to the normal
course of pain treatment, where progressively larger doses of
analgesics, particularly narcotic analgesics, are required to
overcome tolerance.
[0139] Usually, combinations of pain medications yield at best
additive or supplemental results. Thus, it is a significant
advantage of the present invention that it allows for a reduction
in the level of a pain medication, without compromising the level
of pain relief.
[0140] The present invention is not to be limited in scope by the
specific embodiments describe herein. Indeed, various modifications
of the invention in addition to those described herein will become
apparent to those skilled in the art from the foregoing description
and the accompanying figures. Such modifications are intended to
fall within the scope of the appended claims.
EXAMPLES
Example 1
TABLE-US-00001 [0141] Table of Some Embodiments of Norketamine and
Opioid Compositions Norketamine Opioid R,S-Norketamine Morphine
R-Norketamine Morphine S-Norketamine Morphine R,S-Norketamine
Codeine R-Norketamine Codeine S-Norketamine Codeine R,S-Norketamine
Fentanyl R-Norketamine Fentanyl S-Norketamine Fentanyl
R,S-Norketamine Methadone R-Norketamine Methadone S-Norketamine
Methadone R,S-Norketamine Buprenophene R-Norketamine Buprenophene
S-Norketamine Buprenophene
Example 2
[0142] Sprague Dawley (about 90 days old; 350 g) male rats were
used (8 rats/drug/experimental group). R,S-norketamine,
S-norketamine, R-norketamine (Yaupon Therapeutics Inc.) and
R,S-ketamine (Sigma) were dissolved in saline and injected
intraperitoneally (IP, 1 ml/kg). Each rat received four doses of a
drug (1, 2, 4, 8 mg/kg; repeated block Latin square design; 48 h
intervals). Saline served as control.
[0143] A sciatic nerve constriction model of peripheral neuropathy
previously employed was used [Benett and Xie, 1988]. Briefly, under
pentobarbital anesthesia (40 mg/kg, IP) the ligation of sciatic
nerve and sham surgery were performed on the left and right hind
paws, respectively. Proximal to the sciatic trifuracation, nerve (7
mm) was freed from adhering tissue and four loose ligatures were
tied around nerve (1 mm apart) with 4.0 chromic gut, barely
constricting the diameter of the nerve. The incision was closed in
layers. Rats showed a mild aversion of the affected paw and a mild
degree of foot drop. No severe motor impairment was observed.
[0144] The analgesic properties of drugs were determined in
neuropathic rats. Responsiveness to both mechanical and thermal
noxious stimulations was determined in separate groups of rats.
Rats were trained on three occasions before initiation of the
study. Experiments were performed on days 7, 9, 11 and 14 of
recovery from surgery (as this is the time of maximal hyperalgesia
[Holtman et al., 2003]). Responses were assessed prior to
(baseline, taken twice) and at 15-120 min after injection. The left
and right paws were tested alternatively in each rat.
[0145] Mechanical hyperalgesia was measured using an increasing
amount of weight to the paw [Randall and Selitto, 1957]. The hind
paw was placed between a flat surface and a blunt pointer in the
Basile Analgesimeter (UGO Basile) and increasing pressure (32 g/s)
was applied to the dorsal side of the paw. Vocalization was used as
end-point [vocalization threshold, VT (g)]. Cut-off at 300 g
prevented tissue damage.
[0146] The thermal hyperalgesia was measured by plantar test which
used a ramp heat stimulus [Hargreaves et al., 1988]. The radiant
heat (60% intensity) was positioned under the glass floor directly
beneath the plantar hind paw in Plantar Stimulator Analgesia Meter
(IITC, Life Science). Latency of paw withdrawal from the heat
source was measured [paw withdrawal threshold, PWT (s)]. A cut-off
at 20 s prevented tissue damage.
[0147] The behavioral effects of drugs were determined in intact
(unoperated) rats. Locomotor activity was determined using the
Opto-Varimex infrared photocell-based activity monitor (Columbus
Instrument). All activities were scored during 5 min sessions,
prior to and 15, 60 and 120 min after injection. All testing were
conducted between 10:00-13:00. Assessments were performed in 48 h
intervals. Ataxia was determined at 0, 15, 10 and 15 min after
injection. The modified behavioral scale [Sturgon et al., 1979] was
used for quantification (Table 1).
TABLE-US-00002 TABLE 1 Behavioral Rating Scale Rating Ataxia 0
Coordinated movement 1 Loss of balance when rearing, jerky movement
2 Frequent falling to side with attempted walking 3 Unable to
walk
[0148] All data were normalized for preinjection baseline values.
Areas under the curves (AUC) were calculated for normalized data.
Maximum possible effect was calculated as % MPE=(post drug
response-baseline/cut off-baseline).times.100. ED.sub.50 was
calculated from % MPE vs. log dose curves. All data were presented
as mean .+-.SEM of 8 rats. The statistical analysis was performed
with use of one and two-way repeated measures analysis of variance
(ANOVA), post hoc Student Newman Keulus (SNK), Dunnan and t
tests.
R,S-Norketamine Produces Dose-Related Antinociception in Rodent
Model Of Neuropathy (Mechanical and Thermal Tests).
[0149] The racemic mixture of norketamine produced dose-related
antinociception in response to both mechanical and thermal noxious
stimuli on the nerve-injured paw. The effect was of rapid onset and
moderate duration (>2 h). No antinociception was observed on the
control paw (sham-operated) [FIG. 1A,B and FIG. 2A,B]. Saline had
no effect on both paws. These data demonstrate that the major
metabolite of ketamine, norketamine, attenuated in a dose-related
fashion the enhanced sensitivity to mechanical and thermal noxious
stimuli (mechanical and thermal hyperalgesia) in neuropathic rats.
This suggests that norketamine blocks NMDA receptor-mediated
sensitization following peripheral nerve injury.
R,S-Norketamine has a Similar Antinociceptive Efficacy as
R,S-Ketamine in Rodent Model of Neuropathy.
[0150] The antinociceptive potencies of R,S-norketamine and
R,S-ketamine were similar on nerve injured paw
(ED.sub.50=11.3.+-.0.23 and 15.8.+-.0.38 mg/kg, respectively)
[FIGS. 4, 19]. This suggests that a major metabolite, norketamine,
contributes significantly to the antinociceptive effect of a parent
drug, ketamine.
S-Norketamine Produced the Greater Antinociceptive Effect than
R-Norketamine in Rodent Model of Neuropathy.
[0151] The S and R enantiomers of norketamine attenuated, in
dose-related fashion, the mechanical and thermal hyperalgesia on
the nerve-injured paw [FIG. 3A,B and FIG. 4A,B]. Neither drug had
effect on sham-operated paw (data not shown). The antinociceptive
efficacy was markedly greater for S-norketamine compared to
R-norketamine (ED.sub.50=7.3.+-.0.18 and 51.1.+-.0.54 mg/kg,
respectively).
There is a Good Correlation Between the Time Courses of
Antinociception and Plasma Levels of S-Norketamine.
[0152] A pilot studies demonstrated that the time curse of plasma
levels of S-norketamine paralleled the time action curve for
antinociception [FIG. 7]. Plasma concentration of S-norketamine
200-700 ng/ml was associated with the significant analgesic effect
after IP administration in rat.
[0153] Unoperated (intact) rats were used to determine whether
excitatory, depressive or no motor effects are observed at doses
that showed the antinociceptive effect in neuropathic rats.
Norketamine has Less Effect on the Activity Level than
Ketamine.
[0154] The effects of norketamine and ketamine on activity level
were dose-related (data not shown). As can be seen, at the highest
dose (8 mg/kg), the motor effect (depressive) was less pronounced
for R,S-norketamine compared to R,S-ketamine. Further, the
locomotor effect was less for S than R isomer of norketamine [FIG.
8].
Norketamine does not Induce Ataxia in Rats.
[0155] The pilot study demonstrated no ataxia after administration
of R,S- or S-norketamine in rats. This was in contrast to marked
ataxia produced by R,S-ketamine [FIG. 9]. These data suggest that
ketamine-induced ataxia is not due to its metabolite,
norketamine.
[0156] These studies demonstrated that: 1) R,S-Norketamine and
R,S-ketamine have similar same-dose effects in a rodent model of
peripheral neuropathy (mechanical and thermal hyperalgesia). The
analgesic properties of R,S-norketamine are mostly residing in the
S isomer. The R isomer appears to be a less potent analgesic drug.
2) The effect on motor performance and sedation is less pronounced
for R,S-norketamine compared to R,S-ketamine. The locomotor effect
of norketamine seems to be due to R enantiomer. Taken together,
S-norketamine appears to have an equal antinociceptive efficacy but
better side effects profile than clinically used ketamine. This
initial feasibility study provided a basis for phase II preclinical
and clinical studies to further characterize norketamine
enantiomers.
Example 3
[0157] A study was undertaken to determine whether S-norketamine
("norKET") enhances the analgesic effect of morphine ("MOR"). (The
side effect profile was determined to be better for the S than the
R enantiomer.) Both drugs were given alone and in combination by
intraperitoneal [IP; S-norketamine=0.75, 1.5, 3 mg/kg and MOR=3
mg/kg] or intrathecal [IT; S-norKET=10, 50, 100 mcg and MOR=0.5
mcg)] routes in male Sprague-Dawley rats. Saline (vehicle) served
as a control. Responsiveness to thermal noxious stimuli was
determined using the tail-flick assay (baseline tail-flick latency
(TFL) .about.2-3 s; cut off TFL=10 s). TFL was determined at 0, 15,
30, 60, 90, and 120 min. Data demonstrated that S-norKET, in doses
that do not produce an antinociceptive effect alone,
dose-dependently potentiated the antinociceptive effect of MOR in
rats. Significant analgesic interaction was observed after
co-administration of MOR and S-norKET either IP or IT (FIGS.
14-18).
[0158] Male Sprague-Dawley rats, approximately 90 days old,
weighting about 300 g were used. Intrathecal catheter: Chronic
catheterization of the spinal subarachnoid space was performed
according to Yaksh and Rudy (1976). Drugs: Morphine sulfate
(Mallinckrodt) and S-norketamine hydrochloride (Yaupon
Therapeutics, Inc.) were dissolved in saline. Saline served as
control. Doses refer to salt forms.
[0159] Graded doses of morphine and S-norketamine alone as well as
a fixed dose of morphine combined with various doses of
S-norketamine were administered intrathecally (IP) or intrathecally
(IT) in volumes equal to 1 ml/kg and 10 .mu.l, respectively. Doses
were balanced by Latin square design: 2.times. (4.times.4).
Injections were made at weekly intervals.
[0160] Doses of morphine and S-norketamine administered alone and
in combination. Drugs were administered by intraperitoneal (IP) or
intrathecal (IT) routes in rats. Saline (dose 0) served as control.
See Table 2, below.
TABLE-US-00003 IP (mg/kg) IT (.mu.g) Morphine 2 5 7 10 0 3 10 30
Norketamine 0 .75 1.5 3 0 10 50 100 Morphine + Norketamine 0 .75
1.5 3 0 10 50 100
[0161] Tail flick latencies (TFL) were measured using a standard
tail-flick apparatus (LifeScience). Preinjection baseline and
cut-off times were equal to 2-3 s and 10 s, respectively. TFL was
assessed twice prior to (baseline) and at fixed time points after
injection. All data were normalized for baseline. The areas under
the time action curves (AUC0-120 min) were calculated for
normalized data. The percent of maximum effect was calculated as %
MPE=[(TFL-baseline)/(10-baseline).times.100] at each time point.
Data are presented as mean .+-.SEM of (n) rats. Data were analyzed
by two-way ANOVA and post-hoc Student-Newman-Keuls (SNK) method.
Level of significance was P.ltoreq.0.5.
[0162] Morphine produced dose-related antinociception in response
to radiant thermal stimulus (tail-flick test) both after IP (2-10
mg/kg) [FIG. 14] and IT (3-30 .mu.g) administration in rats [FIG.
15]. S-Norketamine did not produce an antinociceptive effect after
IP (0.75-3 mg/kg) [FIG. 16A] or IT (10-100 .mu.g) [FIG. 16B]
administration in rats (tail-flick test). S-Norketamine, in IP
doses that do not produce an antinociceptive effect alone (0.75-3
mg/kg, IP), dose-dependently potentiated the antinociceptive effect
of a low dose morphine (3 mg/kg; IP) [FIG. 17]. Morphine (3 mg/kg,
IP) in combination with S-norketamine (3 mg/kg; IT) produced the
maximum antinociceptive effect (% MPE=100%). The effect of this
magnitude (% MPE=100%) was achieved after administration of
approximately three-fold higher dose of morphine alone (10 mg/kg,
IP) [FIG. 17B vs. FIG. 14B]. The time action curves appear to be
longer after morphine plus S-norketamine than morphine alone (IP
route) [FIG. 17A vs. FIG. 14A].
[0163] S-Norketamine, in IT doses that do not produce an
antinociceptive effect alone (10-100 .mu.g, IT), dose-dependently
potentiated the antinociceptive effect of a low dose morphine (0.5
.mu.g; IT) [FIG. 18]. Morphine (0.5 .mu.g, IT) in combination with
S-norketamine (100 .mu.g, IT) produced greater antinociceptive
effect (% MPE=80%) than this produced by the sixty-fold higher dose
(30 .mu.g, IT) of morphine alone (% MPE=60%) [FIG. 18B vs. FIG.
18B].
[0164] A likely synergistic antinociceptive interaction was
observed after coadministration of morphine and S-norketamine
either by peripheral (IP) or central (IT) routes in rats. The
ability of S-norketamine to enhance morphine analgesia (IP) was
greater than that previously demonstrated for ketamine-morphine
(IP) interaction in rats (Holtman et al., 2003). These findings are
of importance in the development of a novel NMDA receptor
antagonist and opioid receptor agonist combination therapy for pain
management, in particular neuropathic pain.
Example 4
Hydrolysis Study Protocol for Norketamine Prodrug
[0165] Stability studies were conducted both in Hanks' buffer of pH
7.4 and human plasma over a period of 48 hrs (n=3). From the stock
solution of 1 mg/ml of norketamine esters and norketamine in
acetonitrile, a series of standard solutions in the concentration
range of 50-1000 ng/ml with acetonitrile were prepared. Hanks'
buffer (300 .mu.L) and plasma (200 .mu.L) were spiked with 10 .mu.L
of different concentrations of both the drug solutions. The Hanks'
buffer samples were vortexed for 30 sec and centrifuged (20 min at
12000 rpm) and the supernatant is transferred to HPLC vials.
[0166] In the case of the plasma samples, 750 .mu.L of acetonitrile
was added and vortexed for 30 sec and centrifuged (20 min at 12000
rpm) and the supernatant removed. The supernatant was evaporated at
37.degree. C. under nitrogen and reconstituted with 400 .mu.L
acetonitrile and transferred to HPLC vials. The HPLC system
consisted of a Perkin Elmer series 200 autosampler and pump and a
785A UV/VIS detector with Turbochrome 6.1 software. A reversed
phase 220.times.4.6 mm Brownlee Spheri 5 VL C-18 5.mu. column and a
guard column were used. The detector was set at a wavelength of 215
nm. The mobile phase consisted of 0.1% trifluoroacetic acid
(adjusted to pH 3 with triethylamine+0.1% sodium heptane sulfonate
and 5% acetonitrile) acetonitrile: (25:75) at a flow rate of 1.5
ml/min. Injection volume was 100 .mu.L and run time was 10
minutes.
[0167] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or alterations of the invention
following. In general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth and as follows in the scope of the appended
claims.
Example 5
[0168] FIG. 19 demonstrates an analgesic response of S-norketamine
HCl and oxycodone alone and in combination. A tail flick test as
described above was administered intrapertoneally to eight
Sprague-Dawley rats as described above. The * symbol denotes a
statistically difference with oxycodone and norketamine combined
versus the two drugs used alone. Data were analyzed with the SNK
method, with P less than 0.05. FIG. 20 illustrates attenuation of
oxycodone tolerance development by administration with
S-norketamine HCl. A tail flick test as described above was
administered intrapertoneally to eight Sprague-Dawley rats as
described above. The * symbol denotes a difference with oxycodone
used alone as compared to the combination of oxycodone with S
norketameine and the +symbol denotes a difference from day 1. Data
were analyzed with the SNK method, with P less than 0.05.
Example 6
[0169] FIG. 21 depicts analgesic response of S-norketamine with
morphine. A tail flick test as described above was administered to
eight Sprague-Dawley rats as described above The * symbol denotes
difference from morphine alone and the + symbol illustrates
difference from S-norketamine alone as compared to the combination
of S norketamine versus morphine. Data were analyzed with post-hoc
SNK method, with P less than or equal to 0.001.
* * * * *